B cell malignancies are serious and frequently fatal illnesses. Some of the genetic changes that lead to lymphoma have been discovered, but many of the other contributing mechanistic details underlying transformation events are not yet known. It is clear, however, that dysregulation of the balance between cell proliferation and programmed cell death is a central feature. Under normal conditions, lymphocytes must strictly regulate growth and apoptosis to provide adequate immunologic defenses against infections on the one hand, and yet not overwhelm the organism with inappropriate cell numbers on the other hand. A large number of signaling molecules have been implicated in homeostatic control of B cells. The complete set of molecules that regulate mature B cell homeostasis is still being discovered and we have studied the molecular mechanisms that underlie B cell growth, function, and death based on the notion that these same regulatory signaling pathways may contribute significantly to aberrant proliferation and resistance to apoptosis in leukemia and lymphoma. Through partnerships with colleagues in Epidemiology and Hematopathology, we are interested in identifying and characterizing new molecules of interest that are relevant to the biology of lymphoma in hopes to identify novel therapeutic targets.
Current Research Topics
There is accumulating evidence that implicate the TNF superfamily members BAFF (BLyS) and APRIL, as well as their receptors, as critical factors for the growth and survival of both normal and malignant B cells. BAFF has been found to be elevated in a number of immune disease models, and there is increasing evidence that it may correlate with pathogenesis of various B cell-related disorders, including B cell malignancies. BAFF and APRIL are expressed in B-cell non-Hodgkin lymphoma (NHL), and the expression of BAFF is associated with an aggressive disease phenotype. The environmental, as well as genetic, requirements that mediate BAFF expression remain to be defined. Through an integrated basic and population science approach we have recently found that genetic variation in the BAFF gene correlates with increased serum BAFF levels and risk if developing B cell NHL. We are now following up on these initial findings and plan to determine if genetic variability in BAFF, the BAFF receptors TACI, BCMA, and BAFF-R, as well as the BAFF related TNF molecule APRIL, are associated with the development of NHL and the clinical outcome of patients. Identification of mutations or SNPs in these genes that are associated with NHL will then be tested for their functional significance.
In addition to our genetic studies, we are also interested in studying the role of APRIL on the biology of NHL B cells. While much effort has focused on BAFF, the biology of APRIL had received less attention and the biologic functions of APRIL are not as well-established as those of BAFF. We have previously shown that NHL B cells express the receptors for APRIL, TACI, and BCMA in a variable fashion. Studies from other labs support a role for APRIL in malignant B cell biology by showing that approximately 40 percent of aged APRIL transgenic mice develop a B cell-associated neoplasia. These studies suggest that APRIL may play an important role in the pathogenesis of B cell malignancies. We now plan to define the role of APRIL on malignant B cell growth and survival and to decipher the downstream signaling targets that transmit its effects.